The goals of the proposed program are a comprehensive analysis of the structural characteristics of lipid and immune complex platelet-activating factors (PAFs), the biochemical prerequisites for their appearance during acute and subacute immunological reactions, the range and mechanisms of their activities on the cellular elements of immunological reactions and their contribution to host defense mechanisms and to tissue destruction. Rabbit basophil PAF and lipid PAFs isolated from human monocytes and the rat peritoneal cavity will be purified to permit the determination of their structures. The unique functional properties of the lipid PAFs and structural analogues and an immune complex PAF isolated from rheumatoid synovial fluid will be used to evaluate the structural determinants of their platelet-directed activities and the biochemical requirements and controls for platelet activation and desensitization. Preliminary studies have suggested the presence of specific membrane receptors for lipid PAFs and future studies will be designed to isolate and study the structure of solubilized components of platelet and leukocyte plasma membrane receptors for PAFs. The elaboration of potent PAFs is characteristic of diverse immunological reactions which elicit an infiltrate consisting of polymorphonuclear and mononuclear leukocytes. Thus, structurally defined PAFs will be employed to examine the modulation of leukocyte chemotaxis and chemokinesis, the expression of membrane receptors, granule exocytosis and the elaboration of oxygenation products of arachidonic acid. The delineation of the biochemical prerequisites for elaboration of PAF by human monocytes and the subcellular localization of this mediator will also permit assessment of the role of PAF as an endogenous intracellular mediator. Similarly, the release and oxygenation of arachidonic acid is critical to certain platelet and leukocyte functions and the modulation of arachidonic acid oxygenation by PAFs as well as the effects of arachidonate products on platelet and mononuclear leukocyte function will be examined in detail.